Autophagy-senescence interplay in kidney disease: mechanistic insights and therapeutic potential.

Abstract

Autophagy and cellular senescence are intimately linked processes that play pivotal roles in renal homeostasis, aging, and disease progression. Autophagy preserves intracellular integrity by degrading damaged organelles, misfolded proteins, and metabolic waste through lysosomal pathways, thereby maintaining energy balance and delaying senescence. However, with advancing age or persistent stress, autophagic activity declines, leading to the accumulation of senescent cells, mitochondrial dysfunction, and chronic inflammation. In the kidney, a metabolically demanding organ, this imbalance contributes to the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI). Senescent cells secrete a senescence-associated secretory phenotype, which amplifies inflammation, fibrosis, and tissue remodeling. The bidirectional interplay between impaired autophagy and cellular senescence exacerbates renal tubular atrophy, glomerulosclerosis, and interstitial fibrosis, thereby promoting CKD progression and maladaptive repair following AKI. Emerging therapeutic strategies, including autophagy activators, senolytics, antioxidants, and stem cell based interventions, have shown promise in restoring cellular homeostasis and delaying renal aging. Nonetheless, challenges remain in achieving cell type specific modulation while avoiding the deleterious effects of excessive activation. This review highlights recent advances in understanding the mechanistic interplay between autophagy and senescence in renal physiology and disease, outlines their contributions to CKD and AKI, and explores evolving therapeutic strategies aimed at restoring autophagic flux and eliminating senescent cells. Targeting the autophagy senescence axis represents a compelling avenue for precision therapy in kidney disease and may redefine future approaches in nephrology.